Hydrate of 5-[4-[2-(N-methyl-N-(2-pyridil)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt

ABSTRACT

A hydrate of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, maleic acid salt, characterized in that it: (i) comprises water in the range of from 0.2 to 1.1% w/w; and (ii) provides an infrared spectrum containing peaks at 764 and 579 cm −1 ; and/or (iii) provides an X-ray powder diffraction (XRPD) pattern substantially as set out in FIG. II; a process for the preparation of such a compound, a pharmaceutical composition containing such a compound and the use of such a compound or composition in medicine.

[0001] This invention relates to a novel pharmaceutical, to a processfor the preparation of the pharmaceutical and to the use of thepharmaceutical in medicine.

[0002] International Patent Application, Publication Number WO94/05659discloses certain thiazolidinedione derivatives having hypoglycaemic andhypolipidaemic activity including5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt (hereinafter also referred to as “Compound (I)”).

[0003] Compound (I) is disclosed solely as an anhydrous form. It has nowbeen discovered that Compound (I) exists in a novel hydrated form whichis particularly suitable for bulk preparation and handling. This can beprepared by an efficient, economic and reproducible process particularlysuited to large scale preparation.

[0004] The novel hydrate also has useful pharmaceutical properties andin particular it is indicated to be useful for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0005] Accordingly, the present invention provides a hydrate of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt (the “Hydrate”) characterised in that the Hydrate:

[0006] (i) comprises water in the range of from 0.2 to 1.1% w/w; and

[0007] (ii) provides an infra red spectrum containing peaks at 764 and579 cm⁻¹; and/or

[0008] (iii) provides an X-ray powder diffraction (XRPD) patternsubstantially as set out in FIG. II.

[0009] Suitably, the water content of the Hydrate is in the range offrom 0.4 to 0.9% w/w, especially 0.5 to 0.6% w/w, for example 0.54% w/wor 0.6% w/w.

[0010] In one favoured aspect, the Hydrate provides an infra redspectrum substantially as set out in accordance with FIG. I.

[0011] The Hydrate can exist in certain dehydrated forms whichreversibly convert to the Hydrate when contacted with water, either inliquid or vapour form. The present invention encompasses all suchreversibly rehydratable forms of the Hydrate.

[0012] The present invention encompasses the Hydrate isolated in pureform or when admixed with other materials, for example the knownanhydrous form of Compound I, the above mentioned reversiblyrehydratable forms or any other material.

[0013] Thus in one aspect there is provided the Hydrate in isolatedform.

[0014] In a further aspect there is provided the Hydrate in pure form.

[0015] In yet a further aspect there is provided the Hydrate incrystalline form.

[0016] The invention also provides a process for preparing the Hydrate,characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt is crystallised from an aqueous alkanolic solvent,preferably containing from 2.0 to 2.5% by volume of water, mostpreferably 2.0 to 2.3%, for example 2.1% by volume of water.

[0017] Suitable aqueous alkanolic solvents include aqueous ethanol,typically aqueous denatured ethanol, and aqueous isopropanol, ormixtures thereof.

[0018] Crystallisation and any recrystallisation is generally carriedout at low to ambient temperature, such as in the range of between 0 to30° C. for example 25° C.; alternatively crystallisation may beinitiated at an elevated temperature, such as in the range of between30° C. and 60° C. for example 35° C., and then completed by allowing thetemperature of the solvent to cool to ambient or low temperature, suchas in the range of between 0 to 30° C. for example 25° C.

[0019] The crystallisation can be initiated by seeding with crystals ofthe Hydrate but this is not essential.

[0020] Compound I is prepared according to known procedures, such asthose disclosed in WO94/05659. The disclosures of WO94/05659 areincorporated herein by reference.

[0021] When used herein the term ‘prophylaxis of conditions associatedwith diabetes mellitus’ includes the treatment of conditions such asinsulin resistance, impaired glucose tolerance, hyperinsulinaemia andgestational diabetes.

[0022] Diabetes mellitus preferably means Type II diabetes mellitus.

[0023] Conditions associated with diabetes include hyperglycaemia andinsulin resistance, especially acquired insulin resistance and obesity.Further conditions associated with diabetes include hypertension,cardiovascular disease, especially atherosclerosis, certain eatingdisorders, in particular the regulation of appetite and food intake insubjects suffering from disorders associated with under-eating, such asanorexia nervosa, and disorders associated with over-eating, such asobesity and anorexia bulimia. Additional conditions associated withdiabetes include polycystic ovarian syndrome and steroid induced insulinresistance.

[0024] The complications of conditions associated with diabetes mellitusencompassed herein includes renal disease, especially renal diseaseassociated with the development of Type II diabetes including diabeticnephropathy, glomerulonephritis, glomerular sclerosis, nephroticsyndrome, hypertensive nephrosclerosis and end stage renal disease.

[0025] As used herein ‘aqueous’ with reference to a given solvent orsolvent mixture refers to a solvent which contains sufficient water toprovide Hydrate i.e having from 0.2 to 1.1% w/w of water.

[0026] As mentioned above the compound of the invention has usefultherapeutic properties: The present invention accordingly the Hydratefor use as an active therapeutic substance.

[0027] More particularly, the present invention provides the Hydrate foruse in the treatment and/or prophylaxis of diabetes mellitus, conditionsassociated with diabetes mellitus and certain complications thereof.

[0028] The Hydrate may be administered per se or, preferably, as apharmaceutical composition also comprising a pharmaceutically acceptablecarrier. The formulation of the Hydrate and dosages thereof aregenerally as disclosed for Compound (I) in International PatentApplication, Publication Number WO94/05659.

[0029] Accordingly, the present invention also provides a pharmaceuticalcomposition comprising the Hydrate and a pharmaceutically acceptablecarrier therefor.

[0030] The Hydrate is normally administered in unit dosage form.

[0031] The active compound may be administered by any suitable route butusually by the oral or parenteral routes. For such use, the compoundwill normally be employed in the form of a pharmaceutical composition inassociation with a pharmaceutical carrier, diluent and/or excipient,although the exact form of the composition will naturally depend on themode of administration.

[0032] Compositions are prepared by admixture and are suitably adaptedfor oral, parenteral or topical administration, and as such may be inthe form of tablets, capsules, oral liquid preparations, powders,granules, lozenges, pastilles, reconstitutable powders, injectable andinfusable solutions or suspensions, suppositories and transdermaldevices. Orally administrable compositions are preferred, in particularshaped oral compositions, since they are more convenient for generaluse.

[0033] Tablets and capsules for oral administration are usuallypresented in a unit dose, and contain conventional excipients such asbinding agents, fillers, diluents, tabletting agents, lubricants,disintegrants, colourants, flavourings, and wetting agents. The tabletsmay be coated according to well known methods in the art.

[0034] Suitable fillers for use include cellulose, mannitol, lactose andother similar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

[0035] Solid oral compositions may be prepared by conventional methodsof blending, filling, tabletting or the like. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations are,of course, conventional in the art.

[0036] Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs,or may be presented as a dry product for reconstitution with water orother suitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0037] For parenteral administration, fluid unit dose forms are preparedcontaining a compound of the present invention and a sterile vehicle.The compound, depending on the vehicle and the concentration, can beeither suspended or dissolved. Parenteral solutions are normallyprepared by dissolving the active compound in a vehicle and filtersterilising before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are also dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum.

[0038] Parenteral suspensions are prepared in substantially the samemanner except that the active compound is suspended in the vehicleinstead of being dissolved and sterilised by exposure to ethylene oxidebefore suspending in the sterile vehicle. Advantageously, a surfactantor wetting agent is included in the composition to facilitate uniformdistribution of the active compound.

[0039] In addition such compositions may contain further active agentssuch as anti-hypertensive agents and diuretics.

[0040] As is common practice, the compositions will usually beaccompanied by written or printed directions for use in the medicaltreatment concerned.

[0041] As used herein the term ‘pharmaceutically acceptable’ embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term ‘pharmaceutically acceptable salt’ embraces aveterinarily acceptable salt.

[0042] The present invention further provides a method for the treatmentand/or prophylaxis of diabetes mellitus, conditions associated withdiabetes mellitus and certain complications thereof, in a human ornon-human mammal which comprises administering an effective, non-toxic,amount of Hydrate to a human or non-human mammal in need thereof.

[0043] Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

[0044] In the treatment and/or prophylaxis of diabetes mellitus,conditions associated with diabetes mellitus and certain complicationsthereof Hydrate may be taken in doses, such as those described above.

[0045] Similar dosage regimens are suitable for the treatment and/orprophylaxis of non-human mammals.

[0046] In a further aspect the present invention provides the use ofHydrate for the manufacture of a medicament for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof.

[0047] No adverse toxicological effects are indicated for the compoundsof the invention in the above mentioned treatments.

[0048] The following examples illustrate the invention but do not limitit in any way.

EXAMPLE 1 Preparation of Hydrate of 5-[4-[2-(N-methyl-N-(2pyridyl)amino)thoxy]benzyl]thiazolidine-2,4-dione, Maleic Acid Salt

[0049]5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dionefree base (4.0 g) and maleic acid (1.40 g, 1.05 molar equivalents) wereheated in denatured ethanol (40 ml) containing additional water (0.51 g,i.e. a total water content of approximately 2.1% (v/v)) to 60° C. andheld at this temperature for 30 minutes during which time a solution wasobtained. The solution was filtered, re-heated to 50° C., and thencooled with stirring at a rate of 1 deg/min, resulting incrystallisation at 35° C. The resulting suspension was cooled to 25° C.and stirred for two hours. The product was filtered, washed with 99%denatured ethanol (8 ml) and dried at 50° C. in vacuo for 24 hours togive the title compound (4.38 g, 82%). The water content of the productwas 0.54% w/w.

[0050] Characterising Data

[0051] The following characterising data was generated for the Hydrate:

[0052] A Infrared

[0053] The infrared absorption spectrum of a mineral oil dispersion ofthe Hydrate was obtained using a Nicolet 710 FT-IR spectrometer at 2cm⁻¹ resolution. Data were digitised at 1 cm⁻¹ interval. The spectrumobtained is shown in FIG. I. Peak positions are as follows: 3129, 2776,1756, 1747, 1706, 1641, 1617, 1586, 1542, 1512, 1413, 1351, 1331, 1290,1264, 1246, 1210, 1182, 1163, 1108, 1078, 1064, 1031, 1005, 975, 955,926, 865, 764, 738, 719, 662, 619, 579, 557, 532, 525, and 508 cm⁻¹.

[0054] B X-Ray Powder Diffraction (XRPD)

[0055] The XRPD pattern of the Hydrate is shown below in FIG. II and asummary of the XRPD angles and calculated lattice spacing characteristicof the Hydrate is given in Table I.

[0056] A PW1710 X-ray powder diffractometer (Cu X-ray source) was usedto generate the spectrum using the following acquisition conditions:Tube anode: Cu Generator tension: 40 kV Generator current: 30 mA Startangle: 3.5° 2θ End angle: 35.0° 2θ Step size: 0.020 Time per step: 4.550s

[0057] TABLE I X-Ray Powder Diffraction Angles and Calculated LatticeSpacing Characteristic of the Hydrate. Diffraction Angle Lattice Spacing(° 2θ) (Angstroms) 7.6 11.65 8.9 9.90 9.7 9.09 15.1 5.85 15.6 5.68 17.05.22 17.5 5.08 17.9 4.96 19.2 4.62 20.1 4.41 20.6 4.30 22.2 4.00 23.83.73 24.4 3.64 25.2 3.54 25.9 3.44 26.7 3.34 27.5 3.25 28.0 3.19 29.92.99 31.5 2.84

1. A hydrate of5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt, characterised in that it: (i) comprises water in therange of from 0.2 to 1.1% w/w ; and (ii) provides an infra red spectrumcontaining peaks at 764 and 579 cm⁻¹; and/or (iii) provides an X-raypowder diffraction (XRPD) pattern substantially as set out in FIG. II.2. A hydrate according to claim 1, wherein the water content is in therange of from 05 to 0.6% w/w.
 3. A hydrate according to claim 1 or claim2, which provides an infra red spectrum substantially in accordance withFIG. I.
 4. A hydrate according to any one of claims 1 to 3, whichprovides an X-ray powder diffraction (XRPD) pattern substantially as setout in FIG. II.
 5. A hydrate according to any one of claims 1 to 4, inisolated form.
 6. A hydrate according to any one of claims 1 to 5, inpure form.
 7. A hydrate according to any one of claims 1 to 6, incrystalline form.
 8. A compound in the form of a rehydratable form of ahydrate according to any one of claims 1 to
 7. 9. A process forpreparing a hydrate according to claim 1, characterised in that5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione,maleic acid salt is crystallised from aqueous ethanol.
 10. A processaccording to claim 11, wherein the aqueous ethanol contains from 2% to2.5% of water by volume.
 11. A pharmaceutical composition comprising aneffective, non-toxic amount of a hydrate according to claim 1 and apharmaceutically acceptable carrier therefor.
 12. A hydrate according toclaim 1, for use as an active therapeutic substance.
 13. A hydrateaccording to claim 1, for use in the treatment and/or prophylaxis ofdiabetes mellitus, conditions associated with diabetes mellitus andcertain complications thereof.
 14. The use of Hydrate for themanufacture of a medicament for the treatment and/or prophylaxis ofdiabetes mellitus, conditions associated with diabetes mellitus andcertain complications thereof.
 15. A method for the treatment and/orprophylaxis of diabetes mellitus, conditions associated with diabetesmellitus and certain complications thereof, in a human or non-humanmammal which comprises administering an effective, non-toxic, amount ofHydrate to a human or non-human mammal in need thereof.